Abstract
BackgroundPolycystic ovary syndrome (PCOS) is a multifactorial endocrinopathy that affects reproduction and metabolism. Mammalian target of rapamycin (mTOR) has been shown to participate in female reproduction under physiological and pathological conditions. This study aimed to investigate the role of mTOR complex 1 (mTORC1) signaling in dehydroepiandrosterone (DHEA)-induced PCOS mice.ResultsFemale C57BL/6J mice were randomly assigned into three groups: control group, DHEA group, and DHEA + rapamycin group. All DHEA-treated mice were administered 6 mg/100 g DHEA for 21 consecutive days, and the DHEA + rapamycin group was intraperitoneally injected with 4 mg/kg rapamycin every other day for the last 14 days of the DHEA treatment. There was no obvious change in the expression of mTORC1 signaling in the ovaries of the control and DHEA groups. Rapamycin did not protect against DHEA-induced acyclicity and PCO morphology, but impeded follicle development and elevated serum testosterone levels in DHEA-induced mice, which was related with suppressed Hsd3b1, Cyp17a1, and Cyp19a1 expression. Moreover, rapamycin also exacerbated insulin resistance but relieved lipid metabolic disturbance in the short term.ConclusionsRapamycin exacerbated reproductive imbalance in DHEA-induced PCOS mice, which characterized by elevated testosterone levels and suppressed steroid synthesis. This underscores the need for new mTORC1-specific and tissue-specific mTOR-related drugs for reproductive disorders.
Highlights
Polycystic ovary syndrome (PCOS) is a multifactorial endocrinopathy that affects reproduction and metabolism
The mammalian target of rapamycin is a conserved serine/threonine kinase of the phosphatidylinositol kinase-related kinase family that regulates cell growth, Guo et al Journal of Ovarian Research (2021) 14:64 metabolism, and autophagy [5]. Mammalian target of rapamycin (mTOR) contains two distinct multiprotein complexes known as mTOR complex 1 and mTOR complex 2, depending on the sensitivity of each molecule to rapamycin [6]. mTORC1 signaling is recognized as an important factor in regulating female reproductive functions, and is indispensable in folliculogenesis, oocyte meiotic maturation, and steroidogenesis [7,8,9,10]
Rapamycin administration did not prevent loss of estrous cyclicity induced by DHEA, which was spent in the pseudodiestrus cycle most of the time (Fig. 1a and b)
Summary
Polycystic ovary syndrome (PCOS) is a multifactorial endocrinopathy that affects reproduction and metabolism. The mammalian target of rapamycin (mTOR) is a conserved serine/threonine kinase of the phosphatidylinositol kinase-related kinase family that regulates cell growth, Guo et al Journal of Ovarian Research (2021) 14:64 metabolism, and autophagy [5]. Inhibition of mTORC1 can protect against diet-induced obesity and enhance insulin sensitivity [11]. Based on these observations, we hypothesize that mTORC1 signaling is involved in both reproductive and metabolic dysfunctions associated with PCOS. Several studies have reported altered expression of mTOR signaling in the ovaries of PCOS mice models and in luteal granulosa cells of patients with PCOS upon stimulation with insulin, with inconsistent conclusions [12, 13]. An mTORC1 inhibitor, was transiently used in a mouse model of PCOS in order to understand the related alterations in ovarian activity and metabolic changes
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